The mechanisms of hydrolysis of the 2-halotryptophans at low pH have now been fully elucidated and reveal the involvement of intramolecular proton transfer in the conversion of the stable indole to the labile indolenine tautomer. An enzyme carboxyl group should also promote indolenine formation, suggesting the indolenine to be the true substrate for certain tryptophan enzymes. The first conclusive support for this concept is found in the demonstration that 2,3-dihydro-L-tryptophan and oxindolyl-L- alanine, analogs of the indolenine tautomer of tryptophan (tetrahedral carbon at C-3), are potent competitive inhibitors of tryptophan synthase and tryptophanase. Furthermore, the two enzymes show opposing specificity for the C-3 diastereoisomers of 2,3-dihydroxy-L-trytophan, suggesting that these enzymes catalyze their reactions via enantiomeric indolenine intermediates. Inhibition of the enzyme aldose reductase represents a new pharmacological approach toward the treatment of late-onset diabetic complications. These complications affect the eye, kidney, nervous system and circulation; they are thought to result from the hyperosomtic effects of high concentrations of sorbitol, in turn resulting from the reduction of the excess glucose symptomatic of diabetes. Our methods for the synthesis of inhibitors of tryptophan-metabolizing enzymes involve spirolactone intermediates which are fairly similar in overall structure to compounds now in clinical trials as aldose reductase inhibitors. The first series of compounds evaluated as inhibitors show the spirolactones to be active only at concentrations 100 times that of commercial inhibitors; on the other hand, the hydroxyacids resulting from ring opening were ca. ten times more active than the lactones, providing a totally new direction for the design of inhibitors.